Background Comparative evidence for efficacy and safety of second‐generation cholinesterase inhibitors (ChEIs) is still sparse. Objectives The purpose of this research is to compare three ChEIs, donepezil, galantamine and rivastigmine, in patients with mild‐to‐moderate Alzheimer's disease (AD). Methods We conducted a systematic review for published articles and included randomised, double‐blind, placebo‐controlled trials and head‐to‐head randomised trials evaluating the efficacy and safety of ChEIs in patients with AD. We examined Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS‐Cog), Neuropsychiatric Inventory (NPI), Clinician's Interview‐Based Impression of Change plus caregiver's input (CIBIC+) and Clinical Global Impression of Change (CGIC) as efficacy endpoints. Withdrawals due to adverse events and number of patients experiencing nausea, vomiting, diarrhoea and dizziness were examined as safety profiles. Network meta‐analyses were sequentially performed for efficacy and safety outcomes based on drug/dose treatment conditions. Results Among the 21 trials included, network meta‐analysis showed that all treatments were significantly more efficacious than placebo in cognition measured by ADAS‐Cog. All treatments except galantamine were significantly more efficacious than placebo in global change in CIBIC+ or CGIC. Across all conditions, no significant efficacy was observed in neuropsychiatric symptoms measured by NPI. Derived hierarchies in the efficacy of treatment conditions were variables across efficacy and safety. Conclusions Our analysis is the first attempt to incorporate available direct and indirect evidence. The results suggest that ChEIs should have significant efficacy for cognition and global change assessment, but the efficacy on neuropsychiatric symptoms is questionable in patients with mild‐to‐moderate AD.